ABSTRACT Kidney diseases are an expanding public health problem, currently affecting 37 million people and are the 9th leading cause of death in the US, while disproportionately accounting for ~27% of Medicare expenditures. Unfortunately, the number of randomized clinical trials has been fewer than all other specialties of internal medicine with very low success rates, likely due to the structural and functional complexity of the kidney. The multicellular architecture and unusual triad of physiological processes characterized by glomerular filtration, tubular secretion, and tubular reabsorption have limited the ability of animal models to recapitulate the diversity of etiologies, mechanisms, and heterogenous manifestations of most human kidney diseases. Additionally, until recently there has been a lack of in vitro models that recapitulate critical aspects of kidney physiology, mimic the unique complexities of specific nephron segments, or assess reparative mechanisms in response to injury. In response to this critical unmet need, our group has pioneered the development of `human kidney on a chip' microphysiological systems (MPS). Our integrated approach for in vitro disease modeling includes differentiating human kidney cells and organoids from diseased patient-derived inducible pluripotent stem cells (iPSCs), CRISPR gene editing, single cell transcriptional profiling and engineered MPS platforms for both living human kidney vascular networks and tubular units. This approach has already led us to achieve new mechanistic insights into the pathogenesis of autosomal dominant polycystic kidney disease (PKD, the leading monogenetic cause of kidney failure) and potential new therapeutic pathways. In parallel, significant efforts led by us are underway in the Nephrotic Syndrome Study Network (known as NEPTUNE) and the Kidney Precision Medicine Project, NIH funded Consortia designed to address the functional heterogeneity of kidney disease by rigorous molecular, histologic and phenotypic characterization of kidney diseases. The NCATS Rare Disease Clinical Network NEPTUNE is testing the precision medicine concept by matching individual molecular profiles from patients to targeted therapy trials. We now propose to leverage these field-leading tools to inform clinical trial design and planning, accounting for human genetic and clinical response heterogeneity for PKD and Focal Segmental Glomerulosclerosis (FSGS), the form of nephrotic syndrome with the most severe patient consequences. Based on our data, we hypothesize that kidney-on-a-chip MPS will manifest patient-specific phenotypic responses in vitro commensurate with clinical trial outcomes in vivo, establishing a robust molecular and cellular basis for kidney precision medicine approaches. We have established a multidisciplinary investigative team with all the field-leading expertise needed to address all technical and experimental challenges.